Hoffmann-la Roche Inc.

Shian-Jan Shiuey

Milan R Uskokovic

Enrico G Baggiolini, Deceased

John Joseph Partridge

Gary A Truitt

Barbara J Baggiolini

Bernard Michael Hennessy

Jefferson Wright Tilley

Enrico G Baggiolini

Gary L Olson

Waleed Danho

Thomas I Doran

Rolf Wagner

David J Nelson

Compounds of the formula ##STR1## wherein R is hydrogen, hydroxy, or fluorine are useful as agents for the treatment of hyperproliferative disorders of the skin such as psoriasis, as agents for the treatment of leukemia, and as agents for the treatment of sebaceous gland diseases, such as, acne and seborrheic dermatitis.

Method of treating hyperproliferative skin disease with Vitamin D3

Method of treating sebaceous gland diseases with vitamin D.sub.3

Compounds of the formula ##STR1## wherein R is hydrogen, hydroxy, or fluorine, and X is H.sub.2 or .dbd.CH.sub.2 are useful as agents for the treatment of hyperproliferative disorders of the skin such as psoriasis, as agents for the treatment of cancer, such as, leukemia, and as agents for the treatment of sebaceous gland diseases, such as, acne and seborrheic dermatitis.

Vitamin D3 fluorinated analogs

Method of treating hyperproliferative skin diseases with fluorinated

Compounds of the formula ##STR1## wherein R is hydrogen, hydroxy, or fluorine, and X is H.sub.2 are useful as agents for the treatment of hyperproliferative disorders of the skin such as psoriasis, as agents for the treatment of cancer, such as, leukemia, and as agents for the treatment of sebaceous gland diseases, such as, acne and seborrheic dermatitis.

Vitamin D3 Flourinated Analogs

This invention is for 1.alpha.-fluoro-25-hydroxy-16-ene-23-yne-cholecalciferol, which can be further characterized by the formula: ##STR1## and which is useful as an agent for the treatment of sebaceous gland diseases such as acne and sebhorreic dermatitis.

1.alpha.-fluoro-25-hydroxy-16-ene-23-yne-cholecalciferol

Compounds of the formula ##STR1## wherein R is hydrogen or hydroxy, R.sub.5 is hydrogen, and A is ##STR2## with the proviso that when A is --C.tbd.C--, R.sub.5 may also be deuterium, are described. The compounds of formula I are useful as agents for the treatment of hyperproliferative disorders of the skin such as psoriasis, as agents for the treatment of neoplastic diseases such as leukemia, and as agents for the treatment of sebaceous gland diseases such as acne or seborrheic dermatitis.

Vitamin D3 analogs

The invention is directed to novel CCK analogs wherein Tryptophan and/or Phenylalamine are substituted with a radical which provides enhanced appetite suppressant activity to the peptide.

CCK analogs with appetite regulating activity

Compounds of the formula ##STR1## wherein R is hydrogen or hydroxy, R.sub.5 is hydrogen, and A is --C.tbd.C--, ##STR2## or --CH.sub.2 --CH.sub.2 --, with the proviso that when A is --C.tbd.C--, R.sub.5 may also be deuterium, are described. The compounds of formula I are useful as agents for the treatment of hyperproliferative disorders of the skin such as psoriasis, as agents for the treatment of neoplastic diseases such as leukemia, and as agents for the treatment of sebaceous gland diseases such as acne or seborrheic dermatitis.

Vitamin D.sub.3 analogs

Compounds of the formula ##STR1## wherein R.sub.1 is hydrogen or hydroxy and R.sub.2 is hydrogen or fluorine are described. The compounds of formula I are useful as agents in the treatment of disease states characterized by metabolic calcium deficiencies. Examplary of such disease states are osteoporosis and renal osteodystrophy.

Vitamin D compounds

1.alpha.,25-Dihydroxy-24R-fluorocholecalciferol and 1.alpha.,25-dihydroxy-24S-fluorocholecalciferol, analogs of 1.alpha.,25-dihydroxy-cholecalciferol which is physiologically the most active metabolite of vitamin D.sub.3, are synthesized in a multistep process from the known substance 1.alpha.,3.beta.-dihydroxyandrost-5-en-17-one. The new analogs are characterized by the ability to increase intestinal calcium transport, increase serum calcium and phosphate concentrations and to increase the deposition of these minerals in bones. These compounds will find a ready application as substitutes for natural 1.alpha.,25-dihydroxycholecalciferol in the treatment of disease states characterized by metabolic calcium and phosphate deficiencies. Exemplary of such disease states are the following: osteosclerosis, anticonvulsant treatment, osteopenia, fibrogenesis-imperfecta ossium, secondary hyperparathyrodism, hypoparathyroidism, hyperparathyroidism, cirrhosis, obstructive jaundice, drug induced metabolism, medullary carcinoma, chronic renal disease, hypophosphatemic VDRR, vitamin D-dependent rickets, sarcoidosis, glucocorticoid antagonism, malabsorption syndrome, steatorrhea, tropical sprue, idiopathic hypercalcemia and milk fever.

Synthesis of 1.alpha.,25-dihydroxy-24R-fluorocholecalciferol and

1.alpha.,25-Dihydroxy-24R-fluorocholecalciferol and 1.alpha.,25-dihydroxy-24S-fluorocholecalciferol, analogs of 1.alpha.,25-dihydroxy-cholecalciferol which is physiologically the most active metabolite of vitamin D.sub.3, are synthesized in a multistep process from the known substance 1.alpha.,3.beta.-dihydroxyandrost-5-en-17-one. The new analogs are characterized by the ability to increase intestinal calcium transport, increase serum calcium and phosphate concentrations and to increase the deposition of these minerals in bones. These compounds will find a ready application as substitutes for natural 1.alpha.,25-dihydroxycholecalciferol in the treatment of disease states characterized by metabolic calcium and phosphate deficiencies. Exemplary of such disease states are the following: osteomalacia, osteoporosis, rickets, osteitis fibrosa cystica, renal osteodystrophy, osteosclerosis, anti-convulsant treatment, osteopenia, fibrogenesis-imperfecta ossium, secondary hyperparathyrodism, hypoparathyroidism, hyperparathyroidism, cirrhosis, obstructive jaundice, drug induced metabolism, medullary carcinoma, chronic renal disease, hypophosphatemic VDRR, vitamin D-dependent rickets, sarcoidosis, glucocorticoid antagonism, malabsorption syndrome, steatorrhea, tropical sprue, idiopathic hypercalcemia and milk fever.

The syntheses of 25,26-dehydro-1.alpha.,24R-dihydroxycholecalciferol and 25,26-dehydro-1.alpha.,24S-dihydroxycholecalciferol and the epimeric mixture which are useful as differentiation inducing agent and anti-proliferation agents are described. 25,26-dehydro-1.alpha.,24R-dihydroxycholecalciferol, 25,26-dehydro-1.alpha.,24S-dihydroxycholecalciferol, and the epimeric mixture are useful in treating osteoporosis, tumors and leukemia.

25,26-dehydro-1.alpha.,24R-dihydroxycholecalciferol and

The present invention relates to a process and intermediates for the preparation of 24,24-difluoro-1.alpha.,25-dihydroxycholecalciferol from the readily-available 1.alpha.,3.beta.-dihydroxyandrost-5-en-17-one which is made by a known microbiological process from 3.beta.-hydroxyandrost-5-en-17-one [R. M. Dodson, A. H. Goldkamp and R. D. Muir, J. Amer. Chem. Soc. 82 4026 (1960)].

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Nutley, NJ, United States of America

Shian-Jan Shiuey